A major class of proteases involved in the etiology of disease are the cysteine proteases. Cysteine proteases share a common proteolytic mechanism that requires a nucleophilic cysteine thiol in the active site of the protease. Examples of cysteine proteases include caspases, which are essential for mediating cellular apotosis, and calpains, a group of calcium-dependent, non-lysosomal cysteine proteases that are involved in a variety of diseases, including cancer. Other important cyteine proteases involved in disease are the cathepsins. Most cathepsins reside in lysosomes where they are activiated by acidic pH. Cathepsins play a vital role in the turnover of cellular proteins. For example, cathepsin L is a major lysosomal protease that is synthesized as a proenzyme and is secreted from cells where it is activated and promotes the degradation of the extracellular matrix and basement membrane required for tumor metastasis. Increased cathepsin L activity is linked to invasive and metastatic cancers including prostate, colorectal and melanoma cancers. This major cysteine protease also plays a role in the pathology of degenerative cartilage and bone disorders such as rheumatoid arthritis, and osteoporosis, and neurological disorders including Alzheimer's. Cathepsin L activity is also reported to be required for SARS coronavirus infection.
In view of the important role of cysteine proteases in mediating a variety of diseases, there is an urgent need to develop potent, efficacious, and pharmaceutically acceptable compounds capable of inhibiting the activity of these proteases.